2-mercapto-3,6-dihydropyrimidine-3-monocarboxylic acids and esters of these acids



Patented Dec. 26, 1950 EEEAB AQ ;6- DI Q Y I NE MQNOCARBOXYLIG ACIDS AND ESTEBS HES AC S Itogcr A. Mathes; and? Floyd D. Stewart, Akron,

Qhio, assignorssto The B. E. Goodrich Com-. p n eWYQrk, N- acom mtio New York,

NuDrawing. Application-September 13; 1949, Serial :No. 115,556

This invention relate fto new and; useful or-t senior mpoundsand pertains; particularly to certain 2 mercapto 3,6 edihydropyrimidine-li-s monocarboxylicacids; and 1 their esters. This inventiqnv also: contemplates. the; method of; preparing' these new compounds-- The compounds of; thi invention are Z-Il'lfilr cen nhfi: ihvdnonv i idinemo ocarbox ic aci s; an stsrs av srthn fior ut a Where R RaRa audit arehvdr eenq r yd o ar n r di al; e s: a yd ca on dic andilc','is adivalent,hydrocarbonradical. These newcomp unds: are: useful intermediates; in the srnthesis: of. or anic: ch mi al: poun s e also useful in pe icidal o posi ions; n ar .88.1 1" as; retarders of: the vulcaniza on :711: 1 hem materials;

These inf-substituted: 2 mercaptol-iitfi -dihydropyrimidines can be easily and; convenientlpprepared: reactin an amin acid oran esten of an amino acid with a ketone having a hydrogen atom in the alphar position; and a thiocyano group in the beta position to the keto group and being otherwise composed exclusively of carbon and hydrogen atoms (such ketonesbeing hereinafter referred to as beta-thiocyano ketones). During this reaction water is split out, ring closure occurs, t;ha 3-substituted mercapto pyrimidine compound;precipitates and is easily obtained in excellent yields,

The above reaction may be represented by the following generic equation:

Beta-thiocyano ketone Amino acid or ester 3 substituted amercapto;

dih-ydropyrimidine where R1, R2, R3-, R4; Ra and R" have theflsigniflcanoe; as. stated above.

Ana desired beta-mimetic, i te s: aving? the formula as, represented in the above reaction qua io m b used to p epa e he f-substituted 2rmercapto-dihydropyrimidines of this invention by the process of, this invention. Thus,

. any or all of R1, R2, R3 may be hydrogen or anx hydrocarbon radical including alkyl, :allgenyl, cycloalkyl, aryl, aralkyl and alkaryl radicals as well, as, other radicals composed exclusively oi carbon and: hydrogen. Similarly, R may be of these hydrocarbon radicals. Betarthiocyano ketones of thislclass, may be prepared by thereaction of an unsaturated ketone having an ole-.- flnic double bond in the alpha-betaposition, with respect to the keto, group, with nascent thio; cyanic acid formed by the interaction of anon,- oxidizing mineral acid, such as dilute sulfuric acidvor hydrochloric acid, with, ammonium thip cyanate or analkali metal thiocyanate. For ex ample, when such alpha-beta unsaturated ketonesas mesityl oxide, phorone, butylidene 3 061 tone. heptylidene acetone, 5-methyl-4sheptenee one-3,5-- ethyl 3.heptene-one- 2 5-ethyl--3.-nona ene-one-2,3 methyl 4 ethyl 3 hexene-one-Q, vinybmethyl ketone, vinyl ethyl ketone, acryloe phenone-,phenyl vinyl, ketone, chalcone, acrylo; naphthone, benzilidene acetone, 4-pheny1-3 bu!- tene-one-2, styryl n-hexyl ketone, among others arerea-cted with thiocyanic acid, the HSCN, adds to the double bond of. these alphar-beta unsatu-i rated ketones. The resulting products are. the beta-thiocyano, ketones which, are the reactants employed in the process of this invention topree pare the. 3-substituted Z-mercaptopyrimidines of this invention. The preferred beta-thiocya-no ketones for usein this invention are those which possess the formula set forth above wherein each of R1, R2 and R3 is hydrogen or an alkyl radical containing from 1 to 6 carbon atoms and R4, is a similar alkylradical. A typical beta-thiocyano ketone isi-methyl 4 thiocyanonentan 2 one prepared by the addition of HSCN to mesityl Oxi e.

The, other reactant employed in the process of this invention may be any amino acid or hydrocarbon ester of an amino acid having theformula as herei-nbefore set forth. Hence, any amino acid or esterof an amino acidwhose com,- ponents other than the nitrogen of the amino group and the oxygen in the carboxy group of the acid and inthe (OCR group of the ester are exclusively carbon and hydrogen atoms. Thus, the amino compounds are composed of one. 111-: trogen atom connected to a carbon atom, two oxygen atoms both connected to a carbon atom different than the one to which, the nitrogen is attached and are otherwise composed exclusively of carbon and hydrogen atoms.

Examples of such compounds are such amino acids as glycine, alpha-alanine, beta-alanine, amino sec.-butyl acetic acid (isoleucine) 4-aminobutyric acid, l-arnino butyric acid, 2-amino butyric acid, 2-amino-1,1 diethyl butyric acid, 1- amino 2,2-dimethyl butyric acid, 3-amino-2,3- diphenyl butyric acid, l-amino-l-ethyl butyric acid, l-amino l-methyl butyric acid (isovaline), l-amino-l-phenyl butyric acid, 3-(o-aminophenyl) butyric acid, l-amino caproic acid, 4-amin0 caproic acid, 5-amino-2,4-dimethyl caproic acid, 5-amino caproic acid, Z-amino-Z-methyl caproic acid, 5-amino-3-methyl caproic acid, l-amino caprylic acid, 5-amino-3,4,4-trimethyl caprylic acid, l-amino capric acid, Z-amino capric acid, alpha-amino cyclohexaneacetic acid, 4-amino cyclohexaneacetic acid, 2-amino cyclohexanecarboxylic acid, p-amino benzoic acid, 3-amino- -ethyl-benzoic acid, p-(Z-aminopropyl) benzoic acid, p,(2-aminoethyl) benzoic acid, p-(3-aminopropyl) benzoic acid, m-aminobenzoic acid, m- (p-aminophenyl) benzoic acid, 4-amino-2-phenyl benzoic acid, o-(p-aminophenyl) benzoic acid, anthranilic acid, 3,5-dimethy1 anthranilic acid, 3,6-dimethyl anthranilic acid, S-phenyl anthranilic acid, 3-amino-2-anthroic acid, 2-amino-lnaphthoic acid, 3-amino-1-naphthoic acid, 6- amino-l-naphthoic acid, s-amino-l-naphthoic acid, 2-amino-5,6,7,8-terahydronaphthoie acid, 4 amino5,6,7,8 tetrahydronaphthoic acid, 1- amino-Z-naphthoic acid, 3-amino-2-naphthoic acid, 1-amino-3-methyl-2-naphthoic acid, 1- amino-G-methyl-2-naphthoic acid, l-amino-lmethyl naphthoic acid, 1-amino-5,6.'I,8tetrahydronaphthoic acid and 3-amino-5,6.7,8-tetrahydronaphthoic acid. The esters of these amino acids which are useful reactants in preparing these new 3-substituted-2-mercaptopyrimidines include the alkyl esters such as the methyl, ethyl, isopropyl and isobutyl esters; the cycloalkyl esters such as the cyclohexyl esters; the aryl esters such as the phenyl and naphthyl esters; and the aralkyl esters such as the benzyl and phenethyl esters.

In carrying out the preparation of these 2- mercaptopyrimidine 3-monocarboxylic acids and esters, the reactants are brought together in any desired manner. Preferably, the reactants are stirred together in the presence of an inert reaction diluent. Such solvents or diluents as water, ether, benzene,,alcohol and hexane among others are suitable reaction diluents. It is not necessary or critical to employ a reaction diluent where either or both reactants are liquid at about room temperature, for the desired reaction will take place when the reactants are merely combined and heated as herein described. But the use of a diluent facilitates processing and hence isdesirable.

In general, heating the reaction mixture to a temperature of about 100 C. in most cases is desirable. When the reaction is carried out at atmospheric pressure, maintainin th reaction I It is also preferred to carry out the reaction in an acidic reaction medium. This ma be accomplished by adding to the reaction mixture when necessary a small amount of mineral acid such as sulfuric acid or hydrochloric acid as a dilute solution; that is, about a 0.01 molar solution of the acid. Under these conditions, the reaction and the subsequent ring closure takes place more rapidly than when the reaction medium is neutral or basic. It is not critical that the reaction medium be acidic, .for the reaction and ring closure will take place when the medium is neutral. When crude beta-thiocyano ketone is obtained by the reaction hereinbefore described, it is sufficiently acid so that the addition of an acid or acidic material is not necessary to obtain the most desirable rate of reaction. Hence, when purified beta-thiocyano ketone, one which has been washed free of acidic materials, is used, it is not sufficiently acidic to cause the reaction to progress at the most desirable rate and some acidic material must be employed to achieve the optimum reaction rate.

The following specific examples are merely illustrative of our invention and are not intended to be a limitation thereon. It will be apparent that the precise proportions of materials employed may be varied as desired in keeping with best operational technique. In each of the examples, the parts are by weight.

EXAMPLE I A mixture containing 18.7 parts of glycine (amino acetic acid), 39.3 parts of (crude) 4-methyl--thiocyanopentan-Z-one and 125 parts of water was heated for six hours at S. to C. A crystalline solid precipitated during the reaction. The reaction mixture was allowed to cool to room temperature and the solid was then recovered by filtration. In this manner, 31 parts of 2-mercapto-4,6,G-trimethyl-3,6-dihydropyrimidine-3-acetic acid were recovered. This compound when purified by recrystallizing from alcohol had a melting point of 175 C. to 176 C. A chemical analysis of this compound gave the following composition which is in agreement with the calculated composition for the named compound.

Percent composition Found Calculated C 50. 47 G 50. 47 H 6. 59 H 6. 55 N 13. 06 N 13. 08 S 15. 03 S 14.

M. W. 210 M. W. 214

Accordingly, this compound has the formula:

CH3 CHa-( J-CH=CCHz N=CNCH2COOH EXAMPLE II Percent composition s: 1.: Found Calculated o 52. .11 .1 G- 52:61.. H 7.00 1 11' not i N? 12:15 a N" 1227 Accordingly; this: compound has; the formula:

EXAMPLE HIl A mixture containing 22.25 parts ofidl-alphaalanine, 39.3 parts of crude, 4-methy1-4ethiocyanopentan-Z-one and 125 parts... oft water; was heated for six hours at 85 C. to 90 C. A crystal: line product formed during the reaction. Aiteri' the reaction mixture had cooled to room tem perature, the solid productawasrarecoveredibycfiltration. In this manner 21.5 parts of theproduct identified as 2-mercapto-4,6,6-trimethy1-3,6-dihydropyrimidine 3-alpha prnpionic: acidlwere'rreecovered having a melting point after subsequent recrystallization from benzene of 191 C. to 192 C. The chemical composition determined? by:- chemical analysis of this compound. is: in agreement with that for the compound named.

Percent composition-a .Rercantwompositifln- By Analysis kl alcnlated Accordingly;- this: compound 1 has ther-formulata A mixture containng 125 parts of watcr; 34225' parts" of p-aminobenzoic acid and 39.3 parts" of 4-methy1-4-thiocyanopentan 2=one was heated forabout six hours at about 90* C. During the reaction a crystalline precipitate formed which was recoveredby filtration. In this manner 4 6.2 parts of 2-mercapto-4,6,6-trimethyl-3,6-dihydropyrimideni 3 p benzoic acid were recovered which whenrecrystallized from chloroform, had a melting point of"209"C'. to 210Ci This product had a chemical composition as determined by analysis thta was in close agreement with the calculated, chemical composition of the named.

composition as shown below,

Percent. composition flwiccordingly, the product has the following forparts of anthranilic acid and 39.3 parts of 4- mula:

CH: ong-' on=c-om sir EXAMPLE VI 2 mercaptol.6,62-trimethyl 3,6 dihydropy rimidine-3-o-methylbenzoate was prepared" by heating to C. a stirred mixture containing 39.3 parts of purifiedx 4rmethyl-4-thiocyanopentan-Z-one, 3738 parts of methyl anthranilate, parts of water and 2 parts of dilute sulfuric acid (about 0.01 molar solution). During two hours of heating a crystalline precipitate formed. When this resulting mixture had. cooled to room temperature, it was a pasty mass. This pasty mass was filtered. and, washed with; hexane. r The filtrate conta ned some unreacted thiocyano ketone indicating that the reaction was not complete. Thiswas probably the cause of the pasty conditioniof the product, Therewas obtained grams of a. bufi colored solid materialwhich on. purification was a colorless crystalline mater al melting at 0-. to 1186 C. chemical analysis ofjthis purified compound gave the following composition: which is in agreement with the calculated composition ofthedesired-product.

Percent composition By Analysis Calculated C 62. 03 C 62. 04 H 6. 21 H 6. 25 N 9. 37 N 9. 65

EXAMPLES V11 T0 XIII 8. I Having"dis'closed our invention by' :wayof speg cific examples which are intended merely asillusja trations and are not intended aslimitations of our invention, we do not desire or intend to limit 5 ourselves solely thereto; for, as hitherto stated; the proportions of the materials utilized as well as the reaction conditions may be 'varied and chemically equivalent compounds. may be used, if desired, without departing from the spirit and 10 scope of our invention as defined in the appended claims.

We claim: 1. A compound having the formula: I

n If: 1?:

R1-CC=(IIR| =(|l-N-R"--COOR;

other amino acids hereinbefore set forth can also be used. The reactants used and the prod- 20 where R1, R2, R3 and R5 are members selected u'cts obtained are as follows:

from the group consisting of hydrogen and mono- Example Beta Thiocyano Ketonc Used Product ll VII (C2H )2CHCHCH2CCHs (C|Hs)rCH-(|JOH=CCH S 0N N=C-N-CH2C 0 OH 5ethyl-4-thiocyanoheptanQ-one S H (From 5 ethyl-3-heptene-2-one+HSCN) 2-mercapto-4-methyl-6 (l-ethylpropyl) 3,6-dlhydropyrimidine-3-acetic acid (H) 02 VI II--. C4HoCH-CHCH2CCH3 C|Hv-CH-(3HCH=C-CH| 02115 S ON N=(IJNOH2O OH 5-ethyl4-thio cyanononan-2-one S H (From 5-etl1yl-3-nonene-2-one-i-HSON) 2-mercapto-4-methyl-6-(l-ethyl amyl)- 3,6-dihydropyrimidine-3-acetic acid 6 IX C5H11CH-OHaCCHr CsHn(|3H-CH=CGH:

5 my N=C--N-CH1C 0 OH 4-thiocyano-nonan-2-one SH (From 3-nonene-2-one-i-HSON) I 2-mercapto-4-methyHi-amyl-Zifi-dihydropyrimidine-B-acetic acid ll X CzH1CH-CHzGCHa C|Hr(IJHCH=O-OH:

S CN N=?N-CH2C 0 OH 4-thiocyano-heptan-2-one S H (From butylidene acetone-l-HSCN) 2-mercapto-4-methyl-6-propyl-3.6-dihydropyrimidine-Ii-acetic acid I! XI CHr-CHz-C-CH3 ('!Ha--CH=CCHg S CN N=C N-CHgCOOH -thiocyano-butan-Z-one S H (From vinyl methyl ketone+HSCN) Z-mercapto-4-methy1-3,6dihydropyrim1dmet l-acetic acid H XII (|3Hz-GH:C-C2Hs CH3-'CH=C'C3H S CN N=(|J N-CH2COOH fi-thiocyano-heptan-Ki-one 8H (From vinyl ethyl ketone+HSCN) v 2-mercapto-4ethyl-3,fi-dihydropyrimidine- -acetic acid (H) xm Gen-om-m-mm 3-cn-on=c i-crm S CN 2-phenyl-2-thlocyanocthyl butyl ketone (From styryl n-butyl keton-i-HSCN) Z-mcrcapto-4 n-butyl-6-p-phenyl-3,6-dihydro- V pyrlmidine-3-acetic acid CH; CH;J3-CH=CCH1 b I=C ,N--R"-COOH SH where R" is a divalent saturated aliphatic hydrocarbon radical. 3. A compound having the formula:

(33a CH:.-CCH=CCH N=C-N-R-C 0 OH in where R" is a divalent aromatic hydrocarbon radical.

4. 2-mercapto 4,6,6 trimethyl 3,6-dihydropyrimidine-S-acetic acid having the formula:

CH3 cna-o-cihc-cm I I=C-N--CH2GOOH H 5. Z-mercapto 4,6,6 trimethyl 3,6-dihydropyrimidine-3-beta-propionic acid of the formula:

CH: cnr-c-orho-cm N=0NCHzGHr-OOOH 6. Z-mercapto 4,6,6 trimethyl 3,6-dihydropyrimidine-Zi-p-benzoic acid having the formula:

C 0 O H 7. 2-mercapto 4,6,6 trimethyl 3,6-dihydro- CH?- --CH=C--CH;

hat in 0 O OH:

8. The process which comprises reacting a betathiocyano ketone of the formula wherein R1, R2, R3 are members selected from the group consisting of hydrogen and monovalent saturated aliphatic hydrocarbon and monovalent aromatic hydrocarbon radicals and R4 is a radical selected from the group consisting of monovalent saturated aliphatic hydrocarbon and monovalent aromatic hydrocarbon radicals, with a compound of the formula wherein R" is a radical selected from the group consisting of divalent saturated aliphatic hydrocarbon radicals and divalent aromatic hydrocarbon radicals and R5 is a member selected from the group consisting of hydrogen and monovalent saturated aliphatic hydrocarbon and monovalent aromatic hydrocarbon radicals, thereby to produce a compound of the formula wherein R1, R2, R3, R4, R5 and R" have the same meaning as set forth hereinabove.

9. The process of claim 8 wherein the reaction is efiected in an acidic aqueous medium.

10. The process of preparing 2-mercapto-4,6,6- trimethyl 3,6 dihydropyrimidine-3-acetic acid which comprises reacting glycine with 4-methyl- 4-thiocyanopentan-2-one.

11. The process of preparing 2-mercapto-4,6,6- trimethyl-3,G-dihydropyrimidine 3-beta-propionic acid which comprises reacting beta-alanine with 4-methyl-thiocyanopentan-2-one.

12. The process of preparing 2-mercapto-4,6,6- trimethyl 3,6 dihydropyrimidine 3-p-benzoic acid which comprises reacting 4-methyl-4-thiocyanopentan-2-one with p-amino benzoic acid.

13. The process of preparing 2-mercapt0-4,6,6- trimethyl-3,6-dihydropyrimidine 3 o methyl benzoate which comprises reacting methyl anthranilate with 4-methy1-4-thiocyanopentan-2- one.

ROGER A. MATHES. FLOYD D. STEWART.

No references cited. 

1. A COMPOUND HAVING THE FORMULA: 